Alkaloid salts and process of making same



Patent June 18, 1929. v

UNITED STATES PATENT OFFICE.

WALTER SCHOELLER, OF BERLIN-WESTENlJ, AND HERBERT SCHOTIE, OF BERLIN- WILMERSDOBF, GERMANY, ASSIGNOBS TO THE FIRM: CHEMISCHE FABRIK AU]? ACTIEN, VORM. E. SCHERING, OF BERLIN, GERMANY.

ALKALOID SALTS AND PROCESS OF MAKING SAME.

No Drawing. Application filed June 20, 1927, Serial No. 200,299, and in Germany June 26, 1926.

Our invention refers to pharmaceutical products and more especially to salts of the solaneae alkaloids and to the method of making same.

In our copending application Serial No.

. 17 5,923, filed March 16, 1927, we have stated that solaneae alkaloids will combine with solutions of camphoric acid in organic solvents, or with camphoric acid salts only in molecular proportion of 1: 1, the products of this combination being well crystallized saltsf We have now ascertained that it is also I possible to produce neutral salts of camphoric acid, phthalic acid, meconic acid, tartaric acid, saccharic acid, etc, and also inorganic acids such as sulfuric acid, sulfur-dioxide, phosphoric acid, and so on.

The invention can be carried out either by simply combining the components in the presence of a solvent and thereafter removing the solvent in a cautious manner or by treat ing an acid salt of a solaneae alkaloid with a further molecule of the same or some other alkaloid in the presence of a solvent which is then also removed in a cautious manner.

We can, however, also roceed in such manner that the solaneae a kaloids and the acid are caused to react with each other in the form of their salts in a suitable solvent'in such manner that the anion of the solaneae alkaloid salt and the kation 0t the'acid are caused to settle down-in the form of a saltlike precipitate which is not readily soluble in the solvent, whereupon the precipitate is separated and the solvent is removed in a cautious manner.

The neutral mixed salts obtained according to this invention are constituted accordmg to the formula alncnanooomx)c-coon-crnN-m,

wherein R, is scopolamin, R hyoscyamin or atropin, and X a radical of a polybasic acid. They possess very valuable therapeutical properties and the same applies to their combinations with other compounds.

Example 1.

1.5 grams scopolamin are dissolved in 5 ccms. n-sulfuric acid and, are combined w th a solution of 1.5 grams hyoscyamin 1n 5 ccms.

n-sulfuric acid. To this mixture is now i i added a solution of lgram camphoric acid in the caldulated quantity of baryta, the 65 barium sulfate is separated by filtration and the filtrate which is now free from sulfuric acid and baryta is evaporated to dryness in vacuo. The product obtained is scopolaminhyoscyamin comphorate,

- 1101c coin (soopolamin) om-do d -n (hyoscyamin) Gila CHa rnc- Hi a syrup which in concentrated solution shows a neutral'reactionwith lakmus. From its watery solution atropin can be recovered by extraction with ether. The phthalate can be obtained in an analogous manner. It is very much alike to the ,camphorate and forms an pil which undergoes hydrolysis in waterysoution. 1

' Example 9.

Molecular quantities of atropin base and scopolamin base in alcoholic solution are combined with an alcoholic solution of tartaric acid, and the alcohol is driven off at ordinary temperature. The product obtained is the neutral atropin-scopolamin tartrate having the formula.

(scopolamln) nozc-cnorr-cnon-co n (atropin) and forming a syrup which readily dissolves in'media containing hydroxyl ions and is readily converted into the acid salts by hydrolysis. The corresponding salt of succinic l acid canbe obtained in an analogous manner. Ewample 3.

. (scopolamin) HOzC-C C-COzH (hyoscyamm) H C OH and forming a syrup showing neutral reactions with lakmus and dissolving readily in 1 solution with sulfuric acid and brought to" alcohol and water. The corresponding salt of terephthalic acid can be obtained in an analogous manner. It has the form of a syrup which is less readily soluble than the meconate.

Example 1;.

An etheric solution of hyoscyamin, scopolamin, and malonic acid is evaporated to dryness at a pressure of 15 mms mercury, the resulting product being hyoscyamin scopolamin malonate having the formula.

' (scopolamin) no c-om-co u (hyoscyamin) and forming an oil which readily dissolves in water and in methyl and ethyl alcohol, but is insoluble in petrol ether.

Example 5.

l A moleculaf mixture of scopolamin and atropin is neutralized in watery alcoholic drjgness in vacuo. There is obtained the sulfatehaving the formula (scopolamin) H2804 (atropin) and forming a solid amorphous hydroscopic mass which dissolves with the greatest ease in media containing hydroxyl ions. The sulfite can be produced in an analogous manner.

Various changes may be made in the details disclosed in the foregoing specification without departing from the invention or sacrificing the advantages thereof.

We claim '11 The method of producing mixed solaneae alkaloid salts of polybasic acids, comprising preparing a solution of equimolecular quantities of two different solaneae alkaloids and of a polybasic acid in a volatile solvent and allowing the solvent to evaporate at low temperature. 1

2. The method of producing mixed solaneae alkaloid salts of polybasic acids, comprising adding to an acid salt of a solaneae alkaloid and a polybasic acid the equimolecular quantity of another solaneae alkaloid in the presence of a volatile solvent and allowing the solvent to evaporate at low temperature.

3. The method of producing mixed solaneae alkaloid salts of polybasic acids, comprising combining equimolecular quantities of two different salts of solaneae alkaloids with the equimolecular quantity of a salt of a polybasic acid in a volatile solvent in such manner that the anion of the alkaloid salts and .the -kation contained in the salt of the polybasic acid form a compound which is not readily soluble in the solvent, separating the deposit from the solvent and evaporating this latter at low temperature.

4. Themethod of producing scopolamin hyoscyamin camphorate comprising dissolving separately equal parts scopolamin and hyoscyamin in sulfuric acid, mixing the solution, adding a solution of 'camphoric acid inbaryta, filtering of the barium sulfate and evaporating the filtrate to dryness in vacuo.

5. -As a new composition of matter, a mixed solaneae alkaloid salt of a polybasic acid having the general formula wherein R and R are two solaneae alkaloids and X a radical of a polybasic acid.

6. As a new composition of matter, a mixed solaneae alkaloid salt of a polybasic acid having the general formula RlH'QU'H-Rh wherein R and R are two different solaneac alkaloids and X a radical of a di-basic organic acid.

7. As a new product, the mixed solaneae alkaloid salt having the formula scopolamin, H- (X)-H-R,

wherein R is a solaneae alkaloid other than scopolamin and X a radical of a d'i-basic organic acid.

8. As a new roduct the mixed solanese alkaloid salt having the formula scopolamin, H(X)H, hyoscyamin,

H010 COzH (scopolamin) OHa- Ci-C-- -H (hyoscyamin) Ion, ornl H10 CH1 being a syrup which in neutral solution shows 'a neutral reaction with litmus.

In testimony whereof. we afiix our signatures.

WALTER SCHOELLER. HERBERT SCHOTTEL 

